According to the European Technology Platform of Nanomedicine, nanomedicine is defined “as the application of Nanotechnology to Health. It exploits the improved and often novel physical, chemical, and biological properties of materials at the nanometric scale. Nanomedicine has potential impact on the prevention, early and reliable diagnosis and treatment of diseases.”
In the context of therapeutic use, in order to ensure an acceptable benefit/risk ratio of the treatment, the delivery of nanomaterials to the target site in the appropriate dosage range is of utmost importance.
Nanoparticles physicochemical parameters, such as their composition, size, core properties, surface modifications (pegylation and surface charge) and targeting ligand functionalization, impact on nanoparticles interactions with biological barriers. All the above listed factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, delaying opsonization, and increasing the extent of tissue specific accumulation. Particularly, nanoparticles surface functionalization has been used to increase residence time in the blood and reduce nonspecific distribution. For instance, it is well established that hydrophilic polymers, most notably poly(ethylene glycol) (PEG), can be grafted, conjugated, or adsorbed on the surface of nanoparticles to form the corona, which provides steric stabilization and confers “stealth” properties such as prevention of protein adsorption. In general, pegylated nanoparticles were found to have longer circulation times and higher levels of tumor accumulation than nonpegylated nanoparticles. Moreover, the chain length, shape, and density of PEG on the particle surface have been shown to be the main parameters affecting nanoparticle surface phagocytosis.
Notably, Gref et al. have systematically studied the effect of PEG chain length in preventing protein adsorption on the surface of nanoparticles. Their results showed that an optimal molecular mass (Mw) range exists (between 2 and 5 kDa) in order to reduce plasma protein adsorption of their PLA-PEG nanoparticles. The most significant reduction of protein adsorption was found for pegylated particles (5 wt %). Interestingly, a threshold of 1-2 nm space between the PEG chains was estimated for minimal protein adsorption.
Similarly, C. Fang et al. have shown the effect of the molecular mass of PEG for passive targeting of stealth poly(cyanoacrylate-co-n-hexadecyl) cyanoacrylate (PHDCA) nanoparticles. PEG 10 kDa was found to be the most efficient size of PEG as compared to PEG 2 kDa and PEG 5 kDa in preventing protein adsorption.
In summary, much has been learned about PEG molecular mass and PEG density of nanoparticles which has led to reduced plasma protein adsorption, opsonization, and nonspecific uptake. In turn, this has resulted in increased nanoparticle circulation half-life and improved therapeutic efficacy of drugs delivered using pegylated nanocarriers.
However, there is still a need for a composition capable of ensuring systematic delivery of the nanoparticles it contains to a target site in the appropriate dosage range in order to ensure an acceptable benefit/risk ratio of the treatment induced by said composition for the subject.